Pharmacokinetics of clopidogrel

Clopidogrel is extensively metabolized, as evidenced by the absence of dete ctable amounts of unchanged clopidogrel in plasma samples in most clinical trials. The major circulating compound is the inactive carboxylic acid deri vative SR26334, and information on the absorption and elimination of clopid ogrel after oral administration is derived from the pharmacokinetics of thi s metabolite. Single-dose pharmacokinetics of SR26334 were investigated in a randomized, dose-proportionality study comparing single 50, 75, 100, and 150 mg oral doses of clopidogrel administered to 12 subjects. Multiple-dose pharmacokinetics of SR26334 were primarily derived from a study carried ou t in 18 subjects treated with clopidogrel 75 mg once daily for 14 days. Fur ther data on multiple-dose pharmacokinetics were provided by the results of a long-term study carried out in a group of 35 subjects who received clopi dogrel 75 mg once daily for 12 weeks. All subjects were healthy male volunt eers and, in all cases, clopidogrel was taken in the morning after an overn ight fast. The mean C-max values (+/-SD) for SR26334 following single doses of 50, 75, 100, and 150 mg were 1.6 +/- 0.30 mg/L, 2.9 +/- 0.68 mg/L, 3.1 +/- 0.94 mg/L, and 4.9 +/- 1.22 mg/L, respectively. The ANOVA performed on dose-normalized C-max Showed no statistically significant dose effect, demo nstrating a dose-proportional increase of C-max in this range of clopidogre l doses. The urinary excretion of SR26334 was low-2.2 to 2.4% of the dose a dministered-and Clr-2-24 remained virtually ally constant at all four doses . Median T-max (0.8-1.0 hour) and mean plasma t(1/2) (7.2-7.6 hours) values were not significantly different between doses. Following repeated dosing with clopidogrel 75 mg, mean (+/-SD) C-trough values (values before dosing) for SR26334 at steady state ranged from 0.8 +/-: 0.04 mg/L to 0.11 +/- 0.0 7 mg/L. These values are similar to those observed during the 12-week admin istration of clopidogrel indicating that steady-state values are reproducib le and that the esterasic biotransformation of clopidogrel into its carboxy lic acid metabolite remains constant over a number of months of treatment.